Osteoporosis is a complex disease characterized by reduced bone strength and increased susceptibility to low trauma fracture. Although a strong genetic contribution to osteoporosis and fracture is well-documented, the genes and allelic variants conferring risk remain largely undefined. While the BMD phenotype has been the focus of most genetic analyses of osteoporosis, there is increasing recognition that BMO may not be the best surrogate measure for skeletal fragility. Engineering principles predict that tissue material properties (bone quality) and the shape and size of bone (geometry) are important determinants of bone strength. Bone strength cannot be directly measured in vivo in humans, but detailed biomechanical studies can be performed in informative mouse populations. Preliminary studies have led us to 11 chromosomal locations that influence whole femoral bone strength in the mouse. Six of these regions are strongly associated with the size, shape and distribution of bone in the plane of bending reflecting the important contribution of geometry to bone strength. However, the remaining 5 loci are devoid of any association with geometry suggesting that genes residing within these regions impact whole bone strength by exerting effects on bone quality. The opportunity to explore and identify the genetic determinants of the intrinsic material properties of bone represents an entirely new realm of skeletal inquiry. We believe that our group is uniquely positioned to make a major contribution in this unexplored field of skeletal genetics. We have the necessary mouse populations available, the experimental techniques in place, and most importantly we have demonstrated that our research strategy will successfully identify relevant candidate genes. Our proposal to fine map femoral bone quality genes and develop unique genetic animal models for isolating the effects of those genes offers an important route to the identification of the underlying genes. Findings in these animal models can then be used to pinpoint candidate genes or pathways for more focused human investigation. Discovery of the genes essential for optimal bone quality would offer tremendous insight into a poorly understood, but critically important component of overall bone strength.